Dry eye, also known generically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren""s disease and cicatricialpemphigoid may also manifest dry eye complications.
Dry eye consists of a variety of conditions of diverse origin which affect the tear film and the ocular surface. Dry eye is a disorder of the precorneal tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort. Symptoms which include burning, stinging and photophobia are associated with clinical signs of interpalpebral surface damage and tear instability hyperosmolarity. Dry eye is a consequence of a variety of pathogenic causes and afflicts individuals with a broad range of severity. However, a common denominator in dry eye patients is the breakdown of the ocular tear film resulting in dehydration and damage to the exposed ocular surface.
Dry eye occurs in patients with Sjogren""s syndrome, an autoimmune disease which destroys the lacrimal gland and reduces tear production. Approximately 75% of people over the age of 65 suffer from dry eye as tear production decreases with the normal aging process. Hormonal changes occurring during pregnancy, lactation, oral contraceptive use, menstruation and menopause can cause dry eye. Dry eye can occur when ocular surface changes occur in rheumatoid arthritis, diabetes, thyroid abnormalities, asthma, cataracts, glaucoma and lupus. Medications which induce dry eye by decreasing tear production include antidepressants, decongestants, antihistamines, antihypertensives, oral contraceptives, diuretics and anti-ulcer agents. Dry eye can result from exposure to smoke, fluorescent lights, air pollution, wind, heaters, air conditioning. Lack of blinking during computer use can elicit signs and symptoms of dry eye. The condition can result from living in a dry climate or exposure to dry conditions such as in airline travel. Dry eye can result from unusual facial anatomy which affects blinking, or irregularities of the cornea which result in uneven tear distribution. Decreased tear lipid production occurs in infection or inflammation of the meibomian glands, resulting in excessive tear evaporation. Decreased corneal sensitivity can also lead to insufficient reflex tearing and decreased blinking. This can occur as a result of trauma to the eye, for example nerve damage due to flap formation in LASIK surgical procedures or from the corneal photoablation effected by such procedures, or in severe keratitis or excessive contact lens wear.
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface of the eye and many of the symptoms outlined above (Lemp, Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal, volume 21, number 4, pages 221-231 (1995)).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Other approaches include the use of ocular inserts that provide a tear substitute or stimulation of endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and dry eye, Contactologia, volume 20(4), pages 145-49 (1998); and Shine and McCulley, Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality, Archives of Ophthalmology, volume 116(7), pages 849-52 (1998). Examples of phospholipid compositions for the treatment of dry eye are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. Nos. 4,744,980 and 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.), and U.S. Pat. No. 5,578,586 (Glonek et al.). U.S. Pat. No. 5,174,988 (Mautone et al.) discloses phospholipid drug delivery systems involving phospholipids, propellants and an active substance.
U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of ocular inserts in the treatment of dry eye. Other semi-solid therapy has included the administration of carrageenans (U.S. Pat. No. 5,403,841, (Lang)) which gel upon contact with naturally occurring tear film.
Another approach involves the provision of lubricating substances in lieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses compositions containing glycerin and propylene glycol for treating dry eye.
Aside from the above efforts, which are directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the underlying dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient""s waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only disruptive and time consuming, but is also potentially very expensive.
The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies introduced in the eye, they can be a source of contamination leading to infections. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be instilled on a regular and frequent basis.
Mucins are proteins which are heavily glycosylated with glucosamine-based moieties. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjunctival epithelium of human eyes (Greiner et al., Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, volume 98, pages 1843-1846 (1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucus from a Non-Goblet-Cell Source, British Journal of Ophthalmology, volume 65, pages 833-842 (1981)). A number of human-derived mucins which reside in the apical and subapical corneal epithelium have been discovered and cloned (Watanabe et al., Human Corneal and Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface, Investigative Ophthalmology and Visual Science, volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe discovered a new mucin which is secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et al., IOVS, volume 36, number 2, pages 337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebaceous material for lubrication and the corneal refraction of light.
Mucins are also produced and secreted in other parts of the body including lung airway passages, and more specifically from goblet cells interspersed among tracheal/bronchial epithelial cells. Certain arachidonic acid metabolites have been shown to stimulate mucin production in these cells. Yanni reported the increased secretion of mucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid (xe2x80x9cHETExe2x80x9d) derivatives (Yanni et al., Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness, International Archives of Allergy And Applied Immunology, volume 90, pages 307-309 (1989)). Similarly,Marom has reported the production of mucosal glycoproteins in human lung by HETE derivatives (Marom et al., Human Airway Monohydroxy-eicosatetraenoic Acid Generation and Mucous Release, Journal of Clinical Investigation, volume 72, pages 122-127 (1983)).
Agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal peptide-stimulated glycocongfugate secretion from conjunctival goblet cells, Experimental Eye Research, volume 63, pages 27-34, (1996)), gefarnate (Nakmura et al., Gefarnate stimulates secretion of mucin-like glycoproteins by corneal epithelium in vitro and protects corneal epithelium from dessication in vivo, Experimental Eye Research, volume 65, pages 569-574 (1997)), liposomes (U.S. Pat. No. 4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones (U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), and retinoids (U.S. Pat. No. 5 5,455,265). However, many of these compounds or treatments suffer from a lack of specificity, efficacy and potency and none of these agents have been marketed so far as therapeutically useful products to treat dry eye and related ocular surface diseases.
U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containing naturally occurring HETEs, or derivatives thereof, and methods of use for treating dry eye. Yanni et al. discovered that compositions comprising HETEs increase ocular mucin secretion when administered to a patient and are thus useful in treating dry eye.
It is known that under certain conditions 15-HETE can be converted by activated leukocytes to Lipoxin A4 (Serhan, C.N., Bioch. Biophys. Acta, volume 1004, page 158 (1989); Serhan, C. N., et al., J. Biol. Chem., volume 261, page 16340 (1986)). It has also been discovered that aspirin treatment of activated leukocytes induces the biosynthesis of 15-epi-Lipoxin A4 from arachidonic acid via the intermediacy of 15R-HETE (Serhan, N. et al., J. Pharmacol. Exp. Ther., volume 287, page 779 (1998), and Serhan, N. et al., Clin. Chem. Lab. Med., volume 37, page 299, (1999)), and that inflammatory processes may contribute to ocular surface abnormalities in dry eye conditions. Stem ME, et al., A unified theory of the role of the ocular surface in dry eye, In: Sullivan et al., eds. Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2, New York, Plenum, 1998, pp. 643-651. Expression of proinflammatory cytokines in tears (Pflugfelder SC, et al., Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjogren ""s syndrome keratoconjunctivitis sicca, Curr. Eye Res. 19(3):201-211 (1999)), and of markers of inflammation on the ocular surface of patients with Sj6gren""s and non-Sjogren""s keratoconjunctivitis sicca has been reported (Baudouin C, et al., Flow cytometry in Impression Cytology Specimens: A new method for evaluation of conjunctival inflammation. Invest Ophthalmol. Vis. Sci. 38:1458-1464 (1997)), and anti-inflammatory steroids have demonstrated therapeutic efficacy in dry eye patients (Marsh P and Pflugfelder SC, Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren""s syndrome, Ophthalmology, 106:811-816 (1999)). Nothing in the foregoing references, however, discloses or suggests an anti-inflammatory contribution by Lipoxin A4 to the preservation of corneal integrity in the dry eye model.
In view of the foregoing, there is a need for an effective, convenient treatment for dry eye that is capable of alleviating symptoms, as well as treating the underlying physical and physiological deficiencies of dry eye.
The present invention is directed to compositions and methods of use. The compounds are particularly useful in the treatment of dry eye-type diseases and disorders requiring the wetting of the eye. More specifically, the present invention discloses the use of Lipoxin A4 and its analogs, the preferred compositions of which are typically administered topically to the eye for the treatment of dry eye.